Exosomal transfer of osteoclast-derived miRNAs to chondrocytes contributes to osteoarthritis progression

Jin LIU*, Xiaohao WU, Jun LU, Guangxin Huang, Lei DANG, Huarui ZHANG, Chuanxin ZHONG, Zongkang Zhang, Dijie LI, Fangfei LI, Chao LIANG, Yuanyuan YU, Bao Ting Zhang, Lin Chen, Aiping LYU*, Ge ZHANG*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Osteoarthritis (OA) is a prevalent aging-related joint disease lacking disease-modifying therapies. Here, we identified an upregulation of circulating exosomal osteoclast (OC)-derived microRNAs (OC-miRNAs) during the progression of surgery-induced OA in mice. We found that reducing OC-miRNAs by Cre-mediated excision of the key miRNA-processing enzyme Dicer or blocking the secretion of OC-originated exosomes by short interfering RNA-mediated silencing of Rab27a substantially delayed the progression of surgery-induced OA in mice. Mechanistically, the exosomal transfer of OC-miRNAs to chondrocytes reduced the resistance of cartilage to matrix degeneration, osteochondral angiogenesis and sensory innervation during OA progression by suppressing tissue inhibitor of metalloproteinase-2 (TIMP-2) and TIMP-3. Furthermore, systemic administration of a new OC-targeted exosome inhibitor (OCExoInhib) blunted the progression of surgery-induced OA in mice. We suggest that targeting the exosomal transfer of OC-miRNAs to chondrocytes represents a potential therapeutic avenue to tackle OA progression.
Original languageEnglish
Pages (from-to)368–384
Number of pages18
JournalNature Aging
Volume1
Issue number4
DOIs
Publication statusPublished - Apr 2021

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